Recent advances in molecular imaging techniques permit researchers to study disease models, new pharmaceuticals, and molecular interactions through in vivo imaging of laboratory animals. Among these imaging technologies, positron emission tomography (PET) provides quantitative measurement of trace amount of radiolabeled biomolecules without intervention. This is extremely useful for establishing biological models and evaluating new treatment interventions. With the broad utilization of transgenic mice to model human diseases, there is an increasing demand in higher-resolution higher- sensitivity imaging technologies in order to identify molecular events within organs or sub-organ structures. In this project, a prototype device will be developed and attached to a commercial animal PET scanner to enable high-sensitivity sub-millimeter-resolution dynamic whole-body mouse PET imaging, a highly desirable but currently unavailable capability to the research community. The feasibility of such approach has been validated through a proof-of-concept prototype. However, several key technologies must be developed before this innovation can become a practical solution for end users. As a result, an academic-industrial partnership is formed to overcome these technical challenges. The specific aims of this project include: (1) Development of sub-millimeter resolution PET detectors based on scintillation crystal arrays and semiconductor photodetectors. (2) Construction of a prototype add-on device with multiple half-rings of high-resolution detectors to provide dynamic and gated imaging capability for whole- body mouse imaging once it is integrated into a Siemens Inveon scanner. (3) Expand the architecture of Siemens Inveon scanner to handle detectors in the add-on device to maximize the overall system sensitivity. (4) Develop calibration and image reconstruction techniques to optimize the resolution and reconstruction time of PET images. (5) Develop correction techniques (such as normalization, attenuation, scatter and dead time correction) to preserve the quantitative accuracy of PET images. If successful, technologies developed in this project may lead to a cost-effective solution for sub-millimeter resolution PET imaging with high sensitivity, which is likely to benefit the molecular imaging research community, particularly those who use transgenic mice to model human diseases. These new discoveries may ultimately be translated to human applications and significantly impact the health of this society.